The unique characteristics of the primate (particularly human) fetal adrenal were first realized in the early 1900s when its morphology was examined in detail and compared with that of other species. The unusual architecture of the human fetal adrenal cortex, with its unique and disproportionately enlarged fetal zone, its compact definitive zone, and its dramatic remodeling soon after birth captured the interest of developmental anatomists. Many detailed anatomical studies describing the morphology of the developing human fetal adrenal were reported between 1920 and 1960, and these morphological descriptions have not changed significantly. More recently, it has become clear that fetal adrenal cortical growth involves cellular hypertrophy, hyperplasia, apoptosis, and migration and is best described by the migration theory, i.e. cells proliferate in the periphery, migrate centripetally, differentiate during their migration to form the functional cortical zones, and then likely undergo apoptosis in the center of the cortex. Consistent with this model, cells of intermediate phenotype, arranged in columnar cords typical of migration, have been identified between the definitive and fetal zones. This cortical area has been referred to as the transitional zone and, based on the expression of steroidogenic enzymes, we consider it to be a functionally distinct cortical zone. Elegant experiments during the 1950s and 1960s demonstrated the central role of the primate fetal adrenal cortex in establishing the estrogenic milieu of pregnancy. Those findings were among the first indications of the function and physiological role of the human fetal adrenal cortex and led Diczfalusy and co-workers to propose the concept of the feto-placental unit, in which DHEA-S produced by the fetal adrenal cortex is used by the placenta for estrogen synthesis. Tissue and cell culture techniques, together with improved steroid assays, revealed that the fetal zone is the primary source of DHEA-S, and that its steroidogenic activity is regulated by ACTH. In recent years, function of the human and rhesus monkey fetal adrenal cortical zones has been reexamined by assessing the localization and ontogeny of steroidogenic enzyme expression. The primate fetal adrenal cortex is composed of three functionally distinct zones: 1) the fetal zone, which throughout gestation does not express 3 beta HSD but does express P450scc and P450c17 required for DHEA-S synthesis; 2) the transitional zone, which early in gestation is functionally identical to the fetal zone but late in gestation (after 25-30 weeks) expresses 3 beta HSD, P450scc, and P450c17, and therefore is the likely site of glucocorticoid synthesis, and 3) the definitive zone, which lacks P450c17 throughout gestation but late in gestation (after 22-24 weeks) expresses 3 beta HSD and P450scc, and therefore is the likely site of mineralocorticoid synthesis. Indirect evidence, based on effects of P450c21 deficiency and maternal estriol concentrations, indicate that the fetal adrenal cortex produces cortiso...

PRs are key mediators of progesterone action in uterine tissues and are essential for normal uterine function. Aberrant PR function (due to abnormal expression and/or function) is a major cause of uterine pathophysiology. Further investigation of the underlying mechanisms of PR isoform action in the uterus is required, as this knowledge will afford the opportunity to create progestin/PR-based therapeutics to treat various uterine pathologies.

The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relative to fetal maturation varies among viviparous species, indicative of phylogenetically different clocks and alarms; but what is clear is that important common pathways must converge to control the birth process. For example, in all species, parturition involves the transition of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically and forcefully contracts, softening the cervical extracellular matrix to allow distensibility and dilatation and thus a shearing of the fetal membranes to facilitate their rupture. We review a number of theories promulgated to explain how a variety of different timing mechanisms, including fetal membrane cell senescence, circadian endocrine clocks, and inflammatory and mechanical factors, are coordinated as initiators and effectors of parturition. Many of these factors have been independently described with a focus on specific tissue compartments.In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the triggering of parturition. Linkage of these processes allows convergence and integration of the gestational clocks and alarms, prompting a timely and safe birth. In summary, we provide a comprehensive synthesis of the mediators that contribute to the timing of human labor. Integrating these concepts will provide a better understanding of human parturition and ultimately improve pregnancy outcomes.

MgSO4 exposure before preterm birth is neuroprotective, reducing the risk of cerebral palsy and major motor dysfunction. Neonatal inflammatory cytokine levels correlate with neurologic outcome, leading us to assess the effect of MgSO4 on cytokine production in humans. We found reduced maternal TNF-α and IL-6 production following in vivo MgSO4 treatment. Short-term exposure to a clinically effective MgSO4 concentration in vitro substantially reduced the frequency of neonatal monocytes producing TNF-α and IL-6 under constitutive and TLR-stimulated conditions, decreasing cytokine gene and protein expression, without influencing cell viability or phagocytic function. In summary, MgSO4 reduced cytokine production in intrapartum women, term and preterm neonates, demonstrating effectiveness in those at risk for inflammation-associated adverse perinatal outcomes. By probing the mechanism of decreased cytokine production, we found that the immunomodulatory effect was mediated by magnesium and not the sulfate moiety, and it was reversible. Cellular magnesium content increased rapidly upon MgSO4 exposure, and reduced cytokine production occurred following stimulation with different TLR ligands as well as when magnesium was added after TLR stimulation, strongly suggesting that magnesium acts intracellularly. Magnesium increased basal IκBα levels, and upon TLR stimulation was associated with reduced NF-κB activation and nuclear localization. These findings establish a new paradigm for innate immunoregulation, whereby magnesium plays a critical regulatory role in NF-κB activation, cytokine production, and disease pathogenesis.

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In human parturition, progesterone withdrawal and estrogen activation are not mediated by changes in progesterone and estrogen levels. Instead, these events could be facilitated by changes in the responsiveness of the myometrium to progesterone and estrogens via changes in PR and ER expression. We hypothesized that functional progesterone withdrawal occurs by increased expression of the type A PR (PR-A), which suppresses progesterone responsiveness, and that functional estrogen activation occurs by increased myometrial expression of ERalpha and/or ERbeta. To test this hypothesis we compared the abundance of mRNAs (assessed by quantitative RT-PCR) encoding PR-A, PR-B, ERalpha, and ERbeta in nonlaboring (n = 12) and laboring (n = 12) term human myometrium. PR-A, PR-B, the PR-A/PR-B mRNA ratio, and ERalpha mRNA were significantly increased in laboring myometrium, whereas ERbeta mRNA was low and unchanged. The PR-A/PR-B mRNA ratio correlated positively with ERalpha mRNA levels in nonlaboring myometrium and with HOXA10 mRNA levels in laboring myometrium. Because progesterone inhibits ERalpha and HOXA10 expression, these findings indicate that myometrial progesterone responsiveness is inversely related to the extent of expression of PR-A relative to PR-B. ERalpha mRNA levels correlated positively with cyclooxygenase type 2 and oxytocin receptor mRNA levels in nonlaboring myometrium, indicating that the increase in ERalpha expression is directly associated with the activation of contraction-associated genes and estrogen responsiveness. These data indicate that in the term human myometrium, responsiveness to progesterone is controlled by the expression of PR-A relative to PR-B and that a significant increase in this ratio underlies functional progesterone withdrawal. Our data also indicate that functional estrogen activation occurs by increased expression of ERalpha and is linked to functional progesterone withdrawal. Interaction between the PR and ER systems in the human myometrium may be critical for the control of human parturition and the coordination of progesterone withdrawal and estrogen activation required for parturition.

In human parturition, progesterone withdrawal and estrogen activation are not mediated by changes in progesterone and estrogen levels. Instead, these events could be facilitated by changes in the responsiveness of the myometrium to progesterone and estrogens via changes in PR and ER expression. We hypothesized that functional progesterone withdrawal occurs by increased expression of the type A PR (PR-A), which suppresses progesterone responsiveness, and that functional estrogen activation occurs by increased myometrial expression of ERalpha and/or ERbeta. To test this hypothesis we compared the abundance of mRNAs (assessed by quantitative RT-PCR) encoding PR-A, PR-B, ERalpha, and ERbeta in nonlaboring (n = 12) and laboring (n = 12) term human myometrium. PR-A, PR-B, the PR-A/PR-B mRNA ratio, and ERalpha mRNA were significantly increased in laboring myometrium, whereas ERbeta mRNA was low and unchanged. The PR-A/PR-B mRNA ratio correlated positively with ERalpha mRNA levels in nonlaboring myometrium and with HOXA10 mRNA levels in laboring myometrium. Because progesterone inhibits ERalpha and HOXA10 expression, these findings indicate that myometrial progesterone responsiveness is inversely related to the extent of expression of PR-A relative to PR-B. ERalpha mRNA levels correlated positively with cyclooxygenase type 2 and oxytocin receptor mRNA levels in nonlaboring myometrium, indicating that the increase in ERalpha expression is directly associated with the activation of contraction-associated genes and estrogen responsiveness. These data indicate that in the term human myometrium, responsiveness to progesterone is controlled by the expression of PR-A relative to PR-B and that a significant increase in this ratio underlies functional progesterone withdrawal. Our data also indicate that functional estrogen activation occurs by increased expression of ERalpha and is linked to functional progesterone withdrawal. Interaction between the PR and ER systems in the human myometrium may be critical for the control of human parturition and the coordination of progesterone withdrawal and estrogen activation required for parturition.

Progesterone suppresses uterine contractility acting through its receptors (PRA/B). The mechanism by which human labour is initiated in the presence of elevated circulating progesterone has remained an enigma since Csapo first theorized of a functional withdrawal of progesterone in 1965. Here we report that in vitro progesterone-liganded nuclear PRB forms a complex including JUN/JUN homodimers and P54nrb/Sin3A/HDAC to repress transcription of the key labour gene, Cx43. In contrast, unliganded PRA paradoxically activates Cx43 transcription by interacting with FRA2/JUND heterodimers. Furthermore, we find that while nuclear progesterone receptor (PR) is liganded during human pregnancy, it becomes unliganded during both term and preterm labour as a result of increased expression of the progesterone-metabolizing enzyme 20α HSD and reduced nuclear progesterone levels. Our data provide a mechanism by which human labour can occur in the presence of elevated circulating progesterone and suggests non-metabolizable progestogen might represent an alternative new therapeutic approach to preterm birth prevention.